Variant summary: COL4A5 c.2917+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Lv_2020). The variant was absent in 180606 control chromosomes. c.2917+1G>C has been reported in the literature as a hemizygous genotype in two patients affected with Alport Syndrome 1, X-Linked Recessive (Knebelman_1996, Groopman_2019) and as a heterozygous genotype in 2 females (proband and mother) with Hematuria, a related phenotype (Lv_2020). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_033380.3(COL4A5):c.2917+1G>C
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(4)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_033380.3(COL4A5):c.2917+1G>C
Variation ID: 24574 Accession: VCV000024574.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.3 X: 108622826 (GRCh38) [ NCBI UCSC ] X: 107866056 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 14, 2024 Jun 28, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_033380.3:c.2917+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_000495.5:c.2917+1G>C splice donor NC_000023.11:g.108622826G>C NC_000023.10:g.107866056G>C NG_011977.2:g.187903G>C LRG_232:g.187903G>C LRG_232t1:c.2917+1G>C LRG_232t2:c.2917+1G>C - Protein change
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- Other names
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- Canonical SPDI
- NC_000023.11:108622825:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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exon loss; Variation Ontology [ VariO:0381]
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| COL4A5 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2613 | 2795 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
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Dec 23, 2022 | RCV000021453.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 28, 2023 | RCV000681779.4 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Sep 16, 2018)
|
criteria provided, single submitter
Method: research
|
not provided
Affected status: yes
Allele origin:
germline
|
Gharavi Laboratory, Columbia University
Accession: SCV000809242.1
First in ClinVar: Sep 30, 2018 Last updated: Sep 30, 2018 |
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Pathogenic
(Dec 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
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X-linked Alport syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819763.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: COL4A5 c.2917+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: COL4A5 c.2917+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Lv_2020). The variant was absent in 180606 control chromosomes. c.2917+1G>C has been reported in the literature as a hemizygous genotype in two patients affected with Alport Syndrome 1, X-Linked Recessive (Knebelman_1996, Groopman_2019) and as a heterozygous genotype in 2 females (proband and mother) with Hematuria, a related phenotype (Lv_2020). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Jun 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004299693.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting … (more)
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 32659759). ClinVar contains an entry for this variant (Variation ID: 24574). This variant is also known as c.3119+1G>C. Disruption of this splice site has been observed in individuals with Alport syndrome (PMID: 8940267, 32659759). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 33 of the COL4A5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). (less)
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Pathogenic
(May 21, 2017)
|
no assertion criteria provided
Method: in vitro
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X-linked Alport syndrome
(X-linked dominant inheritance)
Affected status: not applicable
Allele origin:
not applicable
|
Institute of Clinical Laboratory Science, Nanjing University Affiliated Jinling Hospital
Accession: SCV001190327.1
First in ClinVar: Sep 24, 2020 Last updated: Sep 24, 2020 |
Comment:
A heterozygous variant c.2767g > t (p.gly923cys) was found in exon 32 of COL4A5 gene in the proband, which is a new variant. Sanger sequencing … (more)
A heterozygous variant c.2767g > t (p.gly923cys) was found in exon 32 of COL4A5 gene in the proband, which is a new variant. Sanger sequencing confirmed that the mutation was co isolated from the disease in the family. In vitro minigene experiment showed that the mutation of c.2767g > t could cause 96 bases missing in exon 33 of COL4A5 gene (less)
Result:
A heterozygous variant c.2767g > t (p.gly923cys) was found in exon 32 of COL4A5 gene in the proband, which is a new variant. Sanger sequencing confirmed that the mutation was co isolated from the disease in the family. In vitro minigene experiment showed that the mutation of c.2767g > t could cause 96 bases missing in exon 33 of COL4A5 gene
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 32659759). ClinVar contains an entry for this variant (Variation ID: 24574). This variant is also known as c.3119+1G>C. Disruption of this splice site has been observed in individuals with Alport syndrome (PMID: 8940267, 32659759). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 33 of the COL4A5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805).
Comment:
A heterozygous variant c.2767g > t (p.gly923cys) was found in exon 32 of COL4A5 gene in the proband, which is a new variant. Sanger sequencing confirmed that the mutation was co isolated from the disease in the family. In vitro minigene experiment showed that the mutation of c.2767g > t could cause 96 bases missing in exon 33 of COL4A5 gene
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
exon loss
|
|
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Institute of Clinical Laboratory Science, Nanjing University Affiliated Jinling Hospital
Accession: SCV001190327.1
|
|
Comment:
Variant summary: COL4A5 c.2917+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Lv_2020). The variant was absent in 180606 control chromosomes. c.2917+1G>C has been reported in the literature as a hemizygous genotype in two patients affected with Alport Syndrome 1, X-Linked Recessive (Knebelman_1996, Groopman_2019) and as a heterozygous genotype in 2 females (proband and mother) with Hematuria, a related phenotype (Lv_2020). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 32659759). ClinVar contains an entry for this variant (Variation ID: 24574). This variant is also known as c.3119+1G>C. Disruption of this splice site has been observed in individuals with Alport syndrome (PMID: 8940267, 32659759). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 33 of the COL4A5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805).
Comment:
A heterozygous variant c.2767g > t (p.gly923cys) was found in exon 32 of COL4A5 gene in the proband, which is a new variant. Sanger sequencing confirmed that the mutation was co isolated from the disease in the family. In vitro minigene experiment showed that the mutation of c.2767g > t could cause 96 bases missing in exon 33 of COL4A5 gene
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Comparative Functional Analysis in vitro of 2 COL4A5 Splicing Mutations at the Same Site in 2 Unrelated Alport Syndrome Chinese Families. | Lv X | Cytogenetic and genome research | 2020 | PMID: 32659759 |
| Diagnostic Utility of Exome Sequencing for Kidney Disease. | Groopman EE | The New England journal of medicine | 2019 | PMID: 30586318 |
| Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy. | Weber S | Pediatric nephrology (Berlin, Germany) | 2016 | PMID: 26809805 |
| Improving mutation screening in familial hematuric nephropathies through next generation sequencing. | Morinière V | Journal of the American Society of Nephrology : JASN | 2014 | PMID: 24854265 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study. | Jais JP | Journal of the American Society of Nephrology : JASN | 2003 | PMID: 14514738 |
| X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. | Jais JP | Journal of the American Society of Nephrology : JASN | 2000 | PMID: 10752524 |
| The clinical spectrum of type IV collagen mutations. | Lemmink HH | Human mutation | 1997 | PMID: 9195222 |
| Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome. | Knebelmann B | American journal of human genetics | 1996 | PMID: 8940267 |
Text-mined citations for rs104886371 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.